1. Field of the Invention
This invention relates to the use of substituted pyrazolo pyrimidines and pyrazolo triazines which selectively bind to mammalian neuropeptide receptors. It further relates to the use of these compounds and compositions containing these compounds in treating conditions related to an excess of neuropeptide Y.
2. Description of the Related Art
Neuropeptide Y (NPY), a 36 amino acid peptide neurotransmitter, is a member of the pancreatic polypeptide class of neurotransmitters/neurohormones which has been shown to be present in both the periphery and central nervous system. NPY is one of the most potent orexogenic agents known and has been shown to play a major role in the regulation of food intake in animals, including humans. At least 6 NPY receptor subclasses have been identified and cloned to date, with two of the subclasses, NPY-1 and NPY-5, thought to be the most important receptor subtypes modulating food intake and energy expenditure. Hence, agents capable of blocking NPY binding at these receptor subtype(s) should have utility in a number of feeding disorders, including obesity, anorexia nervosa, bulimia nervosa; obesity-related disorder including but not limited to insulin resistance, diabetes, hyperlipidemia, and hypertension, as well as other indications for treatment where blockade of NPY activity is beneficial.
Grundemar and Hakanson. TiPS, May 1994 [Vol. 15], 153-159, state that, in animals, neuropeptide Y is a powerful stimulus of food intake, and an inducer of vasoconstriction leading to hypertension. They further point out that low levels of neuropeptide Y (NPY) are associated with loss of appetite. These reports clearly indicate that compounds that inhibit the activity of this protein will reduce hypertension and appetite in animals.
EP0759441 and U.S. Pat. No. 5,576,337 report that physiological disorders related to an excess of neuropeptide Y include:
disorders or diseases pertaining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure; conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, and operations and sugery in the gastrointestinal tract;
cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemmorrhage, depression, anxiety, schizophrenia, and dementia;
conditions related to pain or nociception;
diseases related to abnormal gastrointenstinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn""s disease;
abnormal drink and food intake disorders, such as anorexia and metabolic disorders;
diseases related to sexual dysfunction and reproductive disorders;
conditions or disorders associated with inflammation;
respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction; and diseases related to abnormal hormone release, such as leutinizing hormone, growth hormone, insulin, and prolactin.
A patent application WO 9535298 entitled xe2x80x9cPreparation and formulation of pyrazolopyrimidine derivatives as analgesicsxe2x80x9d [Shoji, Yasuo; Inoue, Makoto; Okamura, Takashi; Hashimoto, Kinji; Ohara, Masayuki; Yasuda, Tsuneo. (Otsuka Pharmaceutical Factory, Inc., Japan). PCT Int. Appl. 89 pp.] as well as JP 10101672 [Adenosine reinforcement agents. Moritoki, Hideki; Iwamoto, Takeshi; Yasuda, Tsuneo. (Otsuka Pharmaceutical Co., Ltd., Japan). Jpn. Kokai Tokkyo Koho 22 pp.] and JP 10101671 [Nitrogen monooxide synthase inhibitors. Moritoki, Hideki; Iwamoto, Takeshi; Yasuda, Tsuneo; 25 pp.]claim a series of aminopyrazolopyrimidines of the formula 
where R1 represents hydrogen, lower alkyl, cycloalkyl, thienyl, furyl, lower alkenyl or phenyl; R2 represents naphthyl, cycloalkyl, furyl, thienyl, pyridyl, phenoxy or phenyl; R3 represents hydrogen, Ph or lower alkyl; R4 represents hydrogen, lower alkyl, lower alkoxycarbonyl, phenyl-substituted lower alkyl, Ph or halogen; R5 represents hydrogen or lower alkyl; R6 represents hydrogen, lower alkyl, phenyl-substituted lower alkyl or benzoyl; Q represents carbonyl or sulfonyl; A represents a single bond, lower alkylene or lower alkenylene; and n represents 0 or 1.
WO 9218504 [Preparation of pyrazolo[1,5-a]pyrimidine derivatives antiinflammatory agents. Inoue, Makoto; Hashimoto, Kinji; Kuwahara, Toshiko; Sugimoto, Yukio; Uesako, Takuji; Funato, Toshiaki. 48 pp.] and JP 03204877 [Preparation of pyrazolo[1,5-a]pyrimidine derivatives as drugs. Inoue, Makoto; Hashimoto, Kinji.; 10 pp.] describe compounds of the formula: 
where R1xe2x80x94R4 may be hydrogen, carboxyl, lower alkoxycarbonyl, phenyl, or lower alkyl or cycloalkyl which may be each substituted with hydroxy, carboxyl or lower alkoxycarbonyl, or alternatively R1 and R2 may combined together to form lower alkylene; R5 represents xe2x80x94SR6 or xe2x80x94NR7R8; and R7 and R8 represent each hydrogen or phenyl which may be substituted with one to three groups, or R7 and R8 may be combined to form, together with the nitrogen atom to which they are bound, 1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, or 1-piperazinyl which may be substituted with hydroxy-lower alkyl or diphenyl-lower alkyl. 
The patent WO 9635690 A1 [Pyrazolo[1,5-a]pyrimidines, process for preparing them, and their use as as pesticides and fungicides. Benoit, Remy; Grote, Thomas; Bayer, Herbert; Mueller, Bernd; Oberdorf, Klaus; Sauter, Hubert; Ammermann, Eberhard; Lorenz, Gisela; Strathmann, Siegfried). 115 pp.] covers compound of the general structure below where n=0 or 1; Yxe2x95x90O, S, NH2, OCH2, SCH2, NH2CH2, CH2O, CH2S, CH2NH2, CH2CH2, CH2:Rb, or C.tplbond.C; and Rxe2x80x2xe2x95x90C(:CHOMe)CO2Me, C(:CHOMe)CONHMe, C(:NOMe)CO2Me, C(:NOCH3)CONHMe, C(:NOMe)CONH2, C(:NOMe)CO2H, C(:CHMe)CO2Me, C(:CHEt)CO2Me, C(:CHOMe)COMe, C(:NOMe)COMe, C(:NOMe)COEt, N(OMe)CO2Me, N(Me)CO2Me, N(Et)CO2Me, C(:NOMe)R where R=2-oxazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl.
Patents EP 347252 [Preparation of triazolo- and pyrazolopyrrolopyrimidines, their use in cacexia treatment, and formulations containing them. Takiguchi, Yo; Ohsumi, Jun; Shimoji, Yasuo; Sasagawa, Kazuhiko. (Sankyo Co., Ltd., Japan) 45 pp] and EP 508549 [New triazolo-pyrimidine and pyrazolo-pyrimidine derivs. for treating cachexia, e.g. 8-benzyl-7,8-dihydro-5-methyl-6H-pyrazole-(1,5A)-pyrrolo-(3,2E)-pyrimidine. Ohsumi, J; Sasagawa, K; Shimoji, Y; Takiguchi, Y. (Sankyo Co., Ltd., Japan) 39 pp] describe compounds of the formula below where Y can be N or CR2 and R1 can be, among other things, substituted alkyl or aryl; R2 is H or halogen; R3 is alkyl or cycloalkyl; R4 and R5 is hydrogen (when dashed line represent single bond) or hydrogen or halogen (when dashed line represents double bond) and R6 is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or alkaryl. 
Likewise, EP 369145 [Preparation of pyrrolo[3,2-e]pyrazolo[1,5-a]pyrimidines as cardiovascular agents and bronchodilators. Tsujitani, Michihiko; Kishii, Kenichi; Inazu, Masato; Morimoto, Toshihiro; Motoki, Yoshiaki; Matsuo, Ichiro. (Pola Chemical Industries, Inc., Japan). 20 pp.] covers structures of the type I below where R1 and R2 can be, among other things, H, alkyl, cycloalkyl, phenyl, or a heterocyclic group and R3 is H or CN. 
This invention provides compounds of the formula: 
Wherein: A is xe2x80x94CHxe2x95x90; or xe2x80x94Nxe2x95x90; or xe2x80x94CRxe2x95x90; X is 
R1 is phenyl, thienyl or pyridyl each optionally substituted with one to three substituents selected from halogen, xe2x80x94OCF3, NO2, CN, hydroxy, alkylalkoxy, COOH, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6 aminoalkyl, aryl, heteroaryl, alkoxy, acyloxy, NR7R8, C1-C4alkylthio, mono-, di-, or trihaloalkyl; or 
wherein;
R is phenyl, substituted phenyl, heteroaryl, C1-C6alkyl, hydrogen, OH, or alkoxy;
R2 is hydrogen or C1-C6alkyl;
R3 and R4 are independently hydrogen, hydroxyl, xe2x80x94N(C1-C3alkyl)2, C1-C6alkyl, nitro, cyano, alkylalkoxy, or aryloxy;
Y is hydrogen, C1-C6alkyl, or pyridyl; n is 1 to 3; and m is 1 to 3; R7 and R8 are H or C1-C6 alkyl;
and with the proviso that if R1 is phenyl, R2 is hydrogen and Y is methyl; X must not be 1-pyrrolidine.
In another aspect, this invention comprises a compound of formula I wherein:
A is xe2x80x94CHxe2x95x90;
n is 0 to 3;
R3 is xe2x80x94H or xe2x80x94CH3;
R4 is xe2x80x94H;
Y is methyl;
R2 is hydrogen; and
R1 is 3-chlorophenyl, 4-chlorophenyl or thienyl.
In another aspect, this invention comprises a compound of Formula I wherein:
A is xe2x80x94CH;
Y is methyl;
n is 2;
R3 and R4are H;
R1 is halogenated phenyl, or trifluoromethoxyphenyl; and
R2 is hydrogen.
In another aspect, this invention comprises a method of inhibiting or alleviating a pathological condition or physiological disorder in a mammal characterized by an excess of neuropeptide Y which comprises administering to a mammal in need of such treatment a neuropeptide Y inhibiting amount of the compound of Formula I, 
wherein A is xe2x80x94CHxe2x95x90; xe2x80x94CRxe2x95x90; or xe2x80x94Nxe2x95x90;
X is NR4R5 where R4 and R5 are selected independently from C1-C8 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C2-C8 alkynyl, C2-C8 alkylalkoxy, alkylaryl, alkylheteroaryl, SO2R7, or SO2NR7R8; each optionally substituted with 1-2 substituents independently selected from R6; or R4 and R5 are taken together to be C3-C8 cycloalkyl, optionally substituted with 1-2 substituents independently selected from R6; C5-C8 cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R6; or a heterocyclic ring containing up to two heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR7xe2x80x94, and xe2x80x94S(O)m-, optionally substituted with 1-3 substituents independently selected from R6; when R4 and R5 are taken together to be C3-C8 cycloalkyl, C5-C8 cycloalkenyl, or a heterocyclic ring as described above then said ring system may be further substituted to form an additional 3-8 membered ring optionally containing up to two heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR7xe2x80x94, and xe2x80x94S(O)m- (m=0-2); R5 may be selected from NR7R8;
R6 is selected independently from hydrogen; halogen, nitro, cyano, hydroxy, alkylalkoxy, COOH, C1-C6 alkyl; C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, alkoxy; acyloxy, NR7NR8, C1-C4 alkylthio, mono-, di-, or trihaloalkyl;
R7 and R8 are independently selected from H, C1-C6 alkyl; C2-C6 alkenyl, alkylalkoxy, C2-C6 alkynyl, aryl, or heteroaryl; and may be joined to form a carbocyclic or heterocyclic ring;
R1 is selected from H, C1-C8 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, or C2-C8 alkynyl, or alkylalkoxy, or R1 and X may be joined together to form a 5-8 membered nitrogen-containing ring optionally containing an additional heteroatom selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR7xe2x80x94, and xe2x80x94S(O)m- and said 5-8 membered ring optionally substituted with 1-2 substituents chosen from R6; said 5-8 membered ring may also contain a carbonyl group; R1 and Y may be joined together to form a 5-8 membered ring optionally containing a heteroatom selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR7xe2x80x94, and xe2x80x94S(O)m- and said 5-8 membered ring optionally substituted with 1-2 substituents chosen from R6, as well as said 5-8 membered ring containing a carbonyl group;
Y is selected from C1-C6 alkyl; alkoxyalkyl, C2-C6 -alkenyl; C2-C6 -alkynyl, alkoxy, aryl, or heteroaryl, or NR4R5 as defined for X;
n is 0 to 3;
R3 is selected from aryl or heteroaryl optionally substituted with 1-3 substituents chosen from R6.
The skilled chemist will be aware that some compounds of formula I may exist in tautomeric forms which are isomers differing in the relative position of a hydrogen atom. All such tautomers and mixtures thereof are included in this invention.
This invention also comprises a method of treating a pathological condition in a mammal characterized by an excess of neuropeptide Y wherein said pathological condition or physiological disorder is a feeding disorder selected from obesity or bulimia.
In another aspect, this invention comprises a method of inhibiting or alleviating a pathological condition or physiological disorder in a mammal wherein said pathological condition or physiological disorder is selected from the group consisting of: disorders or diseases pertaining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure;
conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, and operations and surgery in the gastrointestinal tract;
cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia, and dementia;
conditions related to pain or nociception;
diseases related to abnormal gastrointenstinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn""s disease;
abnormal drink and food intake disorders, such as anorexia and metabolic disorders;
diseases related to sexual dysfunction and reproductive disorders;
conditions or disorders associated with inflammation;
respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction; and diseases related to abnormal hormone release, such as leutinizing hormone, growth hormone, insulin, and prolactin.
This invention provides a method of inhibiting or alleviating a pathological condition in a mammal characterized by an excess of neuropeptide Y wherein said mammal is a dog or cat.
This invention also includes a pharmaceutical composition for inhibiting or alleviating a pathological condition or physiological disorder in a mammal characterized by or associated with an excess of neuropeptide Y, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formulae I and II but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
In another aspect, this invention provides a compound selected from the group consisting of:
7-Pyrrolidin-1-yl-5-methyl-2-phenyl-pyrazolo[1,5-a]pyrimidine;
7-Azetidin-1-yl-5-methyl-2-phenyl-pyrazolo[1,5-a]pyrimidine;
5-Isopropyl-2-phenyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine;
5-Ethyl-2-phenyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine;
2-Phenyl-5-pyridin-2-yl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine;
5-Methyl-7-pyrrolidin-1-yl-2-thiophen-2-yl-pyrazolo[1,5-a]pyrimidine;
2-(3-Chloro-phenyl)-5-methyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine;
2-(4-Chloro-phenyl)-5-methyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine;
5-Methyl-7-pyrrolidin-1-yl-2-(4-trifluoromethoxy-phenyl)-pyrazolo[1,5-a]pyrimidine;
2,5-Diphenyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine;
[4-(5-Methyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidin-2-yl)-phenyl]-methanol;
2-(4-Chloro-phenyl)-5-methyl-7-(2-methyl-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidine;
2-(4-Chloro-phenyl)-5-methyl-7-piperidin-1-yl-pyrazolo[1,5-a]pyrimidine;
{1(S)-[2-(4-Chloro-phenyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-pyrrolidin-3-yl}-dimethyl-amine;
{1(R)-[2-(4-Chloro-phenyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-pyrrolidin-3-yl}-dimethyl-amine;
2-(4-Chloro-phenyl)-5-methyl-7-(2-methyl-piperidin-1-yl)-pyrazolo[1,5-a]pyrimidine;
1-[2-(4-Chloro-phenyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-pyrrolidin-3-ol;
2-[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-5-methyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine;
Benzyl-[4-(5-methyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidin-2-yl)-benzyl]-amine; and
5-Methyl-2-pyridin-4-yl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine.
The term xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of formula I. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of carboxylic acid groups and hydrochloride salts of amino groups. Other pharmaceutically acceptable salts of amino groups are hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. The preparation of such salts is described below.
The compounds of the present invention may have asymmetric carbon atoms. Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.
The compounds of formula I that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
Those compounds of formula I that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula I. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
As used herein, the term xe2x80x9calkylxe2x80x9d means a straight or branched saturated carbon chain of the specified number of carbon atoms. xe2x80x9cCycloalkylxe2x80x9d means a carbocyclic ring of the designated number of carbon atoms. Each cycloalkyl ring may be optionally substituted with one to three R groups wherein R is C1-C6 alkyl.
xe2x80x9cHalogenxe2x80x9d means F, Cl, Br or I.
The preparation of compounds of Formula I of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses describing the preparation of the compounds of the invention are shown in the following Schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those in the art. Purification procedures include crystallization and normal phase or reverse phase chromatography. 
Condensation of an 3-aminopyrazole (A) with a beta-keto ester (Y=carbon) of the type (II) under dehydrating conditions (e.g. refluxing AcOH) affords 7-hydroxy pyrazolo[1,5-a]pyrimidines of the formula (III). Subsequent conversion of the hydroxy compound to the 7-chloro compound (IV) using a chlorinating reagent such as POCl3, followed by displacement of the chlorine by a nitrogen nucleophile affords 7-amino pyrazolo[1,5-a]pyrimidines of the general structure (I). Similarly, condensation of a malonate diester (Yxe2x95x90OR for (II)) with an aminopyrazole (I), follow by bis-chlorination affords the dichloride (IV; Yxe2x95x90Cl). Further nucleophilic displacements affords compounds of the type (I) where Y can be N or O. 
Condensation of an 3-aminopyrazole with an iminoether (Y=carbon) of the type (V) under dehydrating conditions (e.g. refluxing AcOH) affords compounds of the formula (VI). Subsequent conversion of the hydroxy compound to the 7-chloro compound (VII) using a chlorinating reagent such as POCl3, followed by displacement of the chlorine by a nitrogen nucleophile affords compounds of the general structure VIII. An alternate synthetic scheme to afford pyrazolo[1,5-a][1,3,5]triazines is outline below. 
Condensation of a cyanoketone of the type (IX) with thiosemicarbazide (X) affords thiocarbamoyl aminopyrazoles of the formula (XI). Subsequent condensation with a carboxylic acid derivative or ortho ester affords compounds of the formula (XII) (Y=carbon), which can be alkylated to afford the S-alkyl derivative (XIII). Further displacement of the S-alkyl moiety by a nitrogen nucleophiles pyrazolo[1,5-a][1,3,5]triazines of the general structure (XIII).